Microvascular dysfunction is a hallmark of several diseases, including coronary artery disease (CAD or coronary atherosclerosis), most of them with high morbidity and mortality rates. Typically, blood supply and oxygen to the heart are affected, with consequences for longevity and quality of life. Furthermore, in the cascade of developing atherosclerosis, the deterioration of microvascular function is considered one of the first pathophysiological changes, occurring before any detectable morphological abnormalities. Thus, microvascular function is a target of choice for the early detection of atherosclerosis and other diseases affecting the heart such as diabetes, obesity, hypertension and hypercholesterolemia.
Currently, tests for coronary and microvascular function are performed using surrogate markers and physical or pharmacological stress (or vasodilatory) agents. Currently used techniques include electrocardiography (ECG), echocardiography, nuclear cardiology imaging (SPECT and PET), computed tomography (CT), and cardiovascular magnetic resonance (CMR). Surrogate markers are related to contractile function, tracer inflow or blood flow measurements. These are expected to indicate reduced macrovascular or microvascular function including the presence or absence of a significant coronary artery stenosis.
However, the use of physical or vasodilatory stress agents or exercise is contraindicated in some patients and pharmacological stress agents have potential dangerous and undesirable side effects and increase scan time and cost. Furthermore, for visualizing the inflow of blood, nuclear imaging uses a radioactive tracer, and CMR applies an intravenous bolus of an MRI contrast agent. This further impairs patient safety (injection, allergies, side effects) and increases scan preparation time and cost.
Myocardial oxygenation has also been used as a marker for ischemia and microvascular dysfunction. Oxygenation-sensitive CMR (OS-CMR) using the blood oxygen-level-dependent (BOLD) effect allows for non-invasive monitoring of changes in myocardial tissue oxygenation. OS-CMR detects changes in haemoglobin oxygenation by making use of the fact that its magnetic properties change when transitioning from oxygenated to deoxygenated status. While oxygenated haemoglobin (oxyHb) is diamagnetic exhibiting a weak stabilization of the magnetic field surrounding the molecule, de-oxygenated haemoglobin (de-oxyHb) is paramagnetic, de-stabilizing the surrounding field and thereby leading to a loss of magnetic field homogeneity, known as the BOLD effect. CMR protocols sensitive to the BOLD effect show a regional oxygenation-sensitive signal intensity (OS-SI or BOLD-SI) drop in tissues with such a relative increase of de-oxyHb, as seen in myocardial ischemia (Bauer et al. 1999; Wacker at al. 1999; Friedrich et al. 2003; Shea et al. 2005).
Several oxygenation-sensitive approaches have been used to detect coronary artery disease, using myocardial oxygenation changes in response to vasodilation by pharmacological agents such as adenosine or dipyridamole as a marker for myocardial ischemia (Friedrich at al. 2003; Fieno at al. 2004; Wacker et al. 1999; Bauer et al. 1999; Shea et al. 2005). While healthy vessels dilate and lead to an increase in myocardial signal intensity (SI), myocardium subtended by stenotic vessels show a blunted increase or a decrease in myocardial BOLD-SI in response to the vasodilatory trigger (Friedrich et al. 2003; Fieno et al. 2004; Wacker et al. 1999). However, these pharmacological agents have undesirable side effects such as bracycardia, arrhythmia, chest pain, bronchospasm, headache, nausea and heat waves. Furthermore, the injection of such vasoactive substances requires intravenous access and the availability of a medical doctor, additional cost for the vasodilatory agent, additional preparation time, and a risk for adverse events related to the injected agent.
Thus there remains a need for methods and systems for assessing the vascular integrity of the heart and diagnosing heart disease.
Summary
Generally, the present disclosure provides a method for assessing the vascular function of the heart and a system for assessing heart function. In addition, disclosed herein is a method of diagnosing heart disease by assessing oxygenation of the heart, which is a reflection of the vascular integrity of the heart.
Disclosed herein is a method of assessing heart function or microvascular and/or macrovascular function in a subject. The method involves measuring a change in oxygenation and/or blood flow in the heart or other organ of a subject in response to at least one breathing maneuver and comparing the change in the oxygenation and/or blood flow compared to a control. An abnormal response in the change in oxygenation and/or blood flow is indicative of reduced heart or microvascular and/or macrovascular function.
Also disclosed is a method of assessing heart function wherein the heart of a subject is imaged while the oxygenation of the heart is altered in response to at least one breathing maneuver. The resulting image is segmented and the signal intensity of a region of interest is compared to a control. An abnormal change in signal intensity compared to the control is indicative of reduced heart function.
The breathing maneuver may be a breath-hold or a period of hyperventilation and may be voluntary or induced by a machine. The control may be a baseline signal intensity which may be obtained prior to or at the start of the breathing maneuver. The control may also be a measured oxygenation or blood flow in a healthy tissue within the image or a measured oxygenation or blood flow in a stored image of a reference tissue. The reference tissue may be a healthy myocardium or other healthy organ or skeletal muscle.
The change in oxygenation may be measured using an oxygen sensitive imaging technique such as blood oxygen level dependent magnetic resonance imaging (BOLD-MRI), nuclear techniques, single-photon emission computed tomography/SPECT, positron emission tomography/PET, computed tomography/CT, echocardiography or other ultrasound, near infrared spectroscopy/NIRS, intravascular blood flow measurements, fractional flow reserve, or impedance measurements of the myocardium or other organ.
The methods disclosed herein may be used to assess microvascular or macrovascular function in the heart or other organ or to assess disease related to microvascular or macrovascular function such as heart disease or diseases of other organs. Heart disease may be ischemic heart disease, coronary heart disease, heart disease caused by arterial hypertension, diabetes mellitus, hypercholesterolemia, obesity, non-ischemic cardiomyopathies, or myocardial inflammation, congenital heart disease, valvular heart disease, stress-induced cardiomyopathy, microvascular dysfunction or coronary artery stenosis.
The methods disclosed herein do not require infusion of a vasodilator in the subject. An abnormal change may be a blunted increase compared to a control value, a lack of increase compared to a control, a decrease compared to a control or an increase compared to a control.
Also disclosed herein is a system for diagnosing heart or other organ function comprising an imaging device and a processor configured to assess heart or other organ function according to the methods disclosed herein.
Also disclosed herein is a method and system for processing imaging data of a tissue in an individual following a change in oxygenation or blood flow in tissue, for assessing tissue function. Test images are registered with a baseline image, providing registered images. The registered images may be compared to assess variations in the change in the tissue in response to changes in oxygenation or blood flow of the tissue shown in the images. The change in oxygenation or blood flow in the tissue may be quantified and plotted in a parametric plot or displayed in a parametric map to assess whether the change in oxygenation or blood flow, corresponding to a change in signal intensity, is abnormal following a stress event or under other conditions, to assess microvascular or macrovascular function.
Also disclosed herein is a method of assessing microvascular or macrovascular function in an individual comprising: providing baseline imaging data for displaying a baseline image of tissue; providing test imaging data for displaying a plurality of test images of the tissue, at least a portion of the test imaging data having been acquired while oxygenation or blood flow in the tissue is altered in response to a stress event; registering the test images against the baseline image, providing a plurality of registered images; comparing the plurality of registered images for assessing at least one of oxygenation and blood flow in the tissue in response to a stress event; wherein an abnormal response to at least one of oxygenation and blood flow in the tissue is indicative of reduced microvascular or macrovascular function in the tissue.
Providing the baseline imaging data may comprise imaging the individual, accessing stored baseline imaging data of the individual, imaging the individual prior to the stress event, imaging the individual at the start of the stress event or imaging the individual following the end of the stress event. Providing the test imaging data comprises imaging the individual following the end of the stress event.
The stress event comprises a breathing maneuver by the individual for altering oxygenation of the tissue. The breathing maneuver may comprise a breath-hold. The breathing maneuver may comprise at least one period of hyperventilation. The breath-hold may be voluntary. The breath-hold may be induced by a machine.
The stress event may not include administration of a vasodilator to the subject.
The tissue may comprise an organ. The tissue may comprise vascular tissue. The vascular tissue may comprise a vascular structure within the organ. The organ may comprise skeletal muscle. The organ may comprise a heart. The baseline image and the test images may each comprise images of a portion of a myocardium of the heart. The test images may comprise images of at least one cardiac cycle. The registered images may comprise registered images based on test imaging data of the heart acquired during a selected period of a cardiac cycle; and comparing the registered images comprises comparing the registered images based on test imaging data of the heart during the selected period. The selected period may comprise a relative point in time within the cardiac cycle. The selected period may comprise a selected phase of the cardiac cycle. The selected phase may comprise systole. The reduced microvascular or macrovascular function may comprise heart disease. The heart disease may comprise ischemic heart disease, coronary heart disease, heart disease caused by arterial hypertension, diabetes mellitus, hypercholesterolemia, obesity, non-ischemic cardiomyopathies, or myocardial inflammation, congenital heart disease, valvular heart disease, stress-induced cardiomyopathy, microvascular dysfunction or coronary artery stenosis.
The baseline imaging data, the test imaging data, or both comprise imaging data acquired by magnetic resonance imaging, nuclear techniques, single-photon emission computed tomography/SPECT, positron emission tomography/PET, computed tomography/CT, echocardiography or other ultrasound, near infrared spectroscopy/NIRS, intravascular blood flow measurements, fractional flow reserve, impedance measurements, or a combination thereof, applied to the tissue. The baseline imaging data, the test imaging data, or both comprise imaging data acquired by blood oxygen level dependent magnetic resonance imaging (BOLD-MRI).
The baseline imaging data and the test imaging data each comprise imaging data from a first imaging modality, and further comprising comparing the registered imaging data with imaging data from a second imaging modality. The first imaging modality and the second imaging modality together each comprise magnetic resonance imaging, nuclear techniques, single-photon emission computed tomography/SPECT, positron emission tomography/PET, computed tomography/CT, echocardiography or other ultrasound, near infrared spectroscopy/NIRS, intravascular blood flow measurements, fractional flow reserve, impedance measurements, or a combination thereof.
The baseline imaging data and the test imaging data each comprise imaging data from a first imaging sequence, and further comprising comparing the registered imaging data with imaging data from a second imaging sequence. The first imaging sequence and the second imaging sequence are each either BOLD MRI, late contrast MRI, T1 MRI, or T2 MRI.
Registering the test image against the baseline image may comprise automatic registration. Registering the test image against the baseline image may comprise semi-automatic registration. Registering the test image against the baseline image may comprise rigid transformation. Registering the test image against the baseline image may comprise non-rigid transformation.
Registering the test images against the baseline image may comprise: segmenting the baseline image for defining at least one region of interest of the tissue, resulting in a segmented baseline image; segmenting the test images for defining the at least one region of interest in each of the test images, resulting in segmented test images; and registering the segmented test images with the segmented baseline image for registering the at least one region of interest in the segmented test images with the at least one region of interest in the segmented baseline image, resulting in a plurality of segmented registered images; comparing the plurality of registered images comprises comparing the segmented registered images for assessing at least one of oxygenation and blood flow in the at least one region of interest; and the abnormal response to at least one of oxygenation and blood flow by the tissue corresponds to the at least one region of interest and is indicative of reduced microvascular or macrovascular function in the tissue in the at least one region of interest. Segmenting the baseline image and the test image may comprise automatic segmentation. Segmenting the baseline image and the test image may comprise semi-automatic segmentation.
Comparing the plurality of registered images may comprise generating a parametric plot of at least one organ parameter for the tissue.
Comparing the plurality of registered images may comprise a pixel-by-pixel analysis to generate a parametric map of at least one parameter relevant to the tissue of interest.
Comparing the plurality of registered images may comprise comparing a signal intensity.
The abnormal response may comprise a blunted increase, a lack of increase, a decrease or an increase.
The registered images may be segmented for defining the at least one region of interest in each of the registered images, resulting in segmented registered images; comparing the plurality of registered images comprises comparing the segmented registered images for assessing at least one of oxygenation and blood flow in the at least one region of interest; and the abnormal response to at least one of oxygenation and blood flow by the tissue corresponds to the at least one region of interest and is indicative of reduced microvascular or macrovascular function in the tissue in the at least one region of interest. Comparing the plurality of registered images comprises comparing a signal intensity of the entire at least one region of interest.
Also disclosed herein is a computer readable medium having instructions encoded thereon for carrying out a method comprising receiving baseline imaging data for displaying a baseline image of tissue; receiving test imaging data for displaying a plurality of test images of the tissue, at least a portion of the test imaging data having been acquired while oxygenation or blood flow in the tissue is altered in response to a stress event; registering the test images against the baseline image, providing a plurality of registered images; comparing the plurality of registered images for assessing at least one of oxygenation and blood flow in the tissue in response to a stress event; and wherein an abnormal response to at least one of oxygenation and blood flow in the tissue is indicative of reduced microvascular or macrovascular function in the tissue. The method may include any of the features described herein.
Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.